The objective of this research project is to clarify the embryotoxic risks of folate deficiency induced by anticonvulsant drugs. The mechanism by which phenytoin disrupts folate metabolism will be investigated. Furthermore, the relationship of these effects and the embryotoxic effects of phenytoin will be determined. We will use the rat and the mouse as animal models. We propose that phenytoin causes folate deficiency by either altering 5,10-methylene THF reductase activity and/or methionine synthetase activity or by increasing the utilization of folates due to the involvement of folates in metabolism of the drug. We will test the hypothesis that phenytoin is embryotoxic by virtue of these effects on folate biochemistry. We will measure changes with phenytoin treatment in hepatic activities of 5,10-methylene THF reductase and methionine synthetase. We will measure indirectly their in vivo activity by determining the rate of formate and histidine oxidation to CO2. Formate and histidine oxidation rates will also be measured in isolated hepatocytes from phenytoin-treated animals. The effect of phenytoin on blood and tissue levels of folates and on the distribution of folate forms will be ascertained. Studies will also be done in pregnant animals and changes in embryo folate levels and embryo folate metabolism will be determined. The role of folates in phenytoin metabolism will be investigated by studying phenytoin metabolism in animals made folate deficient by dietary manipulations. Embryotoxicity studies will be conducted and in these studies we will determine the relationship between phenytoin-induced folate deficiency and embryotoxicity. Attempts will be made to modulate the embryotoxicity of phenytoin with compounds which restore folate metabolism to normal.